title: Hydrocortisone reduces the beneficial effects of toll-like receptor 2 deficiency on survival in a mouse model of polymicrobial sepsis.
abstract: BACKGROUND
  Toll-like receptors (TLRs) play a crucial role in early host defense against microorganisms. Toll-like receptor 2 (TLR2) polymorphisms have a prevalence of 10%; functional defects of TLR2 are associated with higher susceptibility toward gram-positive bacteria, and TLR2 deficiency has been associated with an impaired adrenal stress response. In the present study, we compared endogenous corticosterone production of wild-type (WT) and TLR2-deficient (TLR2) mice and analyzed survival after hydrocortisone therapy during sepsis induced by cecal ligation and puncture (CLP).
  
  
  METHODS
  Male C57BL/6J (WT); and B6.129-Tlr2tm1Kir/J (TLR2) mice were subjected to CLP or sham operation and randomly assigned to postoperative treatment with either hydrocortisone (5 mg/kg) or vehicle (n = 10 mice/group). Survival was documented for an observation period of 48 h. Endogenous corticosterone production following hydrocortisone treatment and lipoteichoic acid (LTA) exposure, interleukin 6 (IL-6) and IL-1β plasma levels, and blood counts were determined following sham operation or CLP using another n = 5 mice/group. Statistical analysis was performed using analysis of variance/Bonferroni.
  
  
  RESULTS
  TLR2 mice exhibited a lack of suppression and an attenuated increase in endogenous corticosterone production following hydrocortisone or LTA treatment, respectively. After CLP, TLR2 mice exhibited an uncompromised adrenal stress response, higher IL-6 levels, and increased survival compared with WT controls (75 vs. 35%; P < 0.05). Hydrocortisone therapy of TLR2 mice completely abolished this advantage (decrease in survival to 45%, P < 0.05 vs. vehicle-treated TLR2 mice) and was associated with decreased IL-1β plasma concentrations.
  
  
  CONCLUSIONS
  Toll-like receptor 2 deficiency is associated with an uncompromised adrenal stress response and increased survival rates during polymicrobial sepsis. Hydrocortisone treatment increases mortality of septic TLR2 mice, suggesting that hydrocortisone therapy might be harmful for individuals with functional TLR2 polymorphisms.
authors.affiliation: *Clinic for Anesthesiology and Intensive Care Medicine; and †Institute for Experimental Surgery, University Hospital Rostock, Rostock, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bergt
authors.forename: Nana-Maria
authors.initials: NM
authors.lastname: Wagner
authors.forename: Manja
authors.initials: M
authors.lastname: Heidrich
authors.forename: Antje
authors.initials: A
authors.lastname: Butschkau
authors.forename: Gabriele E F
authors.initials: GE
authors.lastname: Nöldge-Schomburg
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
authors.forename: Jan P
authors.initials: JP
authors.lastname: Roesner
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000096:biosynthesis / Q000097:blood; D004195:Disease Models, Animal; D025461:Feedback, Physiological / Q000502:physiology; D006854:Hydrocortisone / Q000627:therapeutic use / Q000633:toxicity*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000382:microbiology* / Q000503:physiopathology; D013045:Species Specificity; D016019:Survival Analysis; D051195:Toll-Like Receptor 2 / Q000172:deficiency*
chemical_list: D018836:Inflammation Mediators; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D003345:Corticosterone; D006854:Hydrocortisone